Benaroya Research Institute at Virginia Mason, Seattle, Wash.
Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Section of Inflammation Repair and Development, National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC and Asthma UK, Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
J Allergy Clin Immunol. 2018 May;141(5):1750-1760.e1. doi: 10.1016/j.jaci.2017.09.041. Epub 2017 Nov 9.
Three years of treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy (GRASS) trial demonstrated that 2 years of treatment through either route was effective in suppressing the response to nasal allergen challenge, although it was insufficient for inhibition 1 year after discontinuation.
We sought to examine in the GRASS trial the time course of immunologic changes during 2 years of sublingual and subcutaneous immunotherapy and for 1 year after treatment discontinuation.
We performed multimodal immunomonitoring to assess allergen-specific CD4 T-cell properties in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-facilitated allergen binding).
All 3 of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years of allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunologic effect. Although frequencies of antigen-specific T2 cells in peripheral blood determined by using HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE antibody-dependent functional assays remained inhibited in part 1 year after discontinuation.
Two years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific T2 cells most closely paralleled the transient clinical outcome, and it is likely that recurrence of the T-cell drivers of allergic immunity abrogated the potential for durable tolerance. On the other hand, the persistence of IgE blocking antibody 1 year after discontinuation might be an early indicator of a protolerogenic mechanism.
舌下或皮下过敏原免疫治疗 3 年已被证明有效，并可诱导长期耐受。变应性鼻炎舌下和皮下免疫治疗反应评估（GRASS）试验表明，两种途径治疗 2 年均能有效抑制鼻过敏原激发的反应，但在停药 1 年后抑制作用不足。
我们在 GRASS 试验中寻求检查舌下和皮下免疫治疗 2 年期间以及治疗停止后 1 年内免疫变化的时间过程。
我们进行了多模式免疫监测，以平行评估过敏原特异性 CD4 T 细胞特性，同时分析鼻过敏原暴露诱导的局部黏膜细胞因子反应以及体液免疫反应，包括 IgE 依赖性嗜碱性粒细胞激活和测量血清抑制活性，用于过敏原-IgE 与 B 细胞结合（IgE 促进过敏原结合）。
在 2 年的过敏原脱敏过程中，这 3 种不同的免疫反应均显示出显著而协调的改变，随后在 3 年时逆转，反映出缺乏持久的免疫效应。虽然使用 HLA Ⅱ类四聚体分析确定的外周血中抗原特异性 T2 细胞的频率最接近临床结果，但 IgE 抗体依赖性功能测定在停药后 1 年仍部分受到抑制。
2 年的过敏原免疫治疗是有效的，但不足以实现长期耐受。过敏原特异性 T2 细胞最接近短暂的临床结果，很可能是过敏免疫的 T 细胞驱动因素的复发破坏了持久耐受的潜力。另一方面，停药后 1 年持续存在 IgE 阻断抗体可能是一种耐受原性机制的早期指标。
